21-heterocyclic carboxylic acid esters of pregnanes



United States Patent ()fiiice 3,314,854 Patented Apr. 18, 1967 tion of Germany No Drawing. Filed Nov. 3, 1964, Ser. No. 408,660 application Germany, Aug. 19, 196i,

Claims priority,

1s Claims. iii. 167 65) ABSTRACT @F THE DTSCLUSURE The invention relates to novel ZI-heterocyclic carboxylic acid esters of pregnanes which possess high antiinflammatory activity and a lower hypophysial inhibiting activity.

This application is a continuation-in-part of our United States patent application No. 216,738, filed August 14, 1962, now abandoned.

The invention relates to novel 2l-carboxylic acid esters of steroids having the formula:

wherein X and X form a radical selected from the group consisting of ethylene and vinylene, R is selected from the group consisting of hydrogen and methyl and together with the l7-hydroxyl group forms the radical steroid alcohols or their simple carboxylic acid esters and surprisingly possess a lower hypophysis inhibiting activity than the said steroid alcohols and simple esters thereof, All prior art steroid derivatives which possess a greater anti-inflammatory activity than.the original steroid also possess a greater hypophysis inhibiting activity.

It is an object of the invention to provide the novel compounds of Formula I.

It is another object of the invention to provide novel anti-infiammatory activity.

These and other objects and advantages of the invention Will become obvious from the following detailed description.

The novel compounds of the invention have the formula:

of ethylene and vinylene, R is selected from gether with the l7-hydroxyl and Y is selected from the group consisting of pyridine-2, 3- and 4-carbonyloxy radicals and pyridine-2,3 and 4- acetoxy radicals.

The novel esters of the invention may be prepared by the usual csterification processes. The corresponding 21- halo-corticosteroids may be reacted with a salt of the desired pyridine carboxyiic acid at elevated temperatures or preferably by reacting the free corticosteroid alcohol with the acid halide of the desired pyridine carboxylic acid in the presence of a solvent such as pyridine and dimethyl-formamide at temperatures of 0 to C. Other methods include reacting the free corticosteroid alcohol with the desired pyridine carboxylic acid anhydride in suppositories, prepared by the usual known processes.

The method of the invention for inhibiting inflammation comprises administering daily an effective amount of a carboxylic acid ester of Formula I. The said carboxylic acid ester may be administered orally, transcutaneously or by application on the skin. The usual useful single ticosteroids. This naturally has grave biological consequences. The esters of Formula I have surprisingly greater anti-inflammatory activity with a lower hypophysis inhibiting activity than the free steroid alcohols.

In the following examples there are described several However, it should be understood that the invention is not intended to be limited to the specific embodiments.

3 EXAMPLE 1 0.5 gm. of 9ot-fluoro-16a-methyl-A -pregnadiene- 11B, 17a-diol-3,20-dione dissolved in 2.5 cc. of pyridine and 0.2 gm. of pyridine-3-carboxylic acid chloride dissolved in 1.5 cc. of dimethylformamide were combined with stirring and the mixture was kept at 45 C. for hours. The reaction mixture was then poured into a mixture consisting of cc. of concentrated hydrochloric acid, cc. of water and cc. of acetone and 0.54 gm. (84% of theory) of 21-(pyridine-3-carbonyloxy)-9o-fiuoro-16otmethyl-A -pregnadiene-11fi,17a-diol-3,20-dione having a melting point of 253 to 257 C. and a specific rotation [a] =+114.5 (dioxane) was obtained.

EXAMPLE II Using the procedure of Example I, 0.5 gm. of 9afluoro 16a methyl-A -pregnadiene-llB,17x,21-triol- 3,20-dione (dexa-methasone) dissolved in 2.5 cc. of pyridine was reacted with 0.2 gm. of pyridine-4-carboxylic acid chloride dissolved in 1.5 cc. of dimethylformamide to obtain 0.54 gm. of theory) of 21-(pyridine-4- carbonyloxy) fiuoro-l6a-methyl-A -pregnadiene- 11f3,17oz-diOl-3,20-di0fl6 having a melting point of 250 252 C. and a specific rotation [a] -'-+193.5 (dioxane).

EXAMPLE III 500 mg. of 9a-fiuoro-A -pregnene-11fi,17ot,21-trio1-3,20- dione and 1 gm. of pyrridyl-2-carboxylic acid were dissolved in 4 cc. of pyridine, and while stirring this mixture phosphorus oxychloride was added dropwise at room temperature. After allowing the reaction mixture to stand for 50 hours at 25 C., the reaction solution was poured into a mixture of water and hydrochloric acid and the mixture was then neutralized with a sodium bicarbonate solution. After extraction with ethyl acetate, concentrating the extract by evaporation, taking up the residue in ethanol and repeating the precipitation with water, the product was recrystallized from ethanol/water to give 80 mg. of 21 (pyridine-Z-carbonyloxy)-9oi-fluoro-A -preg- Ilene-11B,17u-diol-3,20-dione having a melting point of 250 C. and a specific rotation [a] :+l83 (methanol).

EXAMPLE IV 0.5 gm. of 9u-fiuoro-A -pregnene-1lfi,17a,21-triol-3,20- dione was added together with 0.9 gm. pyridine-3-carboxylic acid anhydride to 2.5 cc. of pyridine and the mixture was heated for 2 hours on a steam bath. After pouring the reaction solution into 15 cc. of water and neutralizing the same with a sodium bicarbonate solution, the oily precipitate which separated out was stirred and separated by vacuum filtration and was recrystallized in aqueous alcohol. 440 mg. (70% of theory) of 21- (pyridine 3 carbonyloxy)-9u-fluoro-A -pregnene-11,8, 1706-d101-3,20-d10116 having a melting point of 253 C. and a specific rotation [u] :\-181.5 (methanol) were obtained.

EXAMPLE V Using the procedure of Example IV, 0.3 gm. of 9ocgm. (84% of theory) of 21-(pyridine-4-carbonyloxy)-901- fiuoro-M-pregnene-l1,8,17a-diol-3,20-dione having a melting point of 233.5 to 234.5 C. and a specific rotation [a] :+181.5 (methanol).

EXAMPLE VI 21 (pyridine 3 acetoxy) 90 fluoro A pregnene- 11,B,17oc-di0l-3,20-di0ne EXAMPLE VII 2] (pyridine 2 carbonyloxy) 9a flu0r0-16a-methyl- A -pregnadiene-11B,1 7a-di0l-3,20-dz'0ne Using the process of Example III, 500 mg. of 9ozfiuoro-l6a-methyl-A -pregnadiene 11fi,17oc,21 triol- 3,20-dione and 1 gm. of pyridine-Z-carboxylic acid dissolved in 4 cc. of pyridine were mixed with phosphorous oxychloride dropwise to obtain 180 mg. (28.5% of theory) of 21 (pyridine- 2 carbonyloxy)-9ot fluoro-16a-methyl- A -pregnadiene-l1fi,17ci-diol-3,20-dione having a melting point of 255.5 C. and a specific rotation [a] =+148 (methanol) EXAMPLE VIII 21 (pyridine 3 acetoxy) 90: fluoro 160a methyl- A -pregnadiene-1lfl,17a-diol-3,2O-dione Using the process of Example III, 500 mg. of 9a-fiuoro- 16a methyl A pregnadiene l1/3,l7a,21 triol 3,20- dione and 1 gm. of pyridine-3-ace tic acid in 6 cc. of pyridine were mixed with 0.2 cc. of thionyl chloride to obtain mg. of 21-(pyridine-3-acetoxy)-9t-fluoro-l6umethyl-A -pregnadiene-11B,17a-diol3,20-dione having a melting point of 199 C. and a specific rotation M1 +36.6 (methanol).

EXAMPLE IX The 16,17acet0nide of 21-(pyridine-.i-carbonyloxy)-9orfluoro A pregnadiene 11,8,16a,17u triol- 3,20- dione 300 mg. of the 16,17-acetonide of 9ot-fiuoro-A -preg nadiene-l113,16,17a-triol-3,20-dione and mg. of the hydrochloride of pyridine-3-carboxylic acid chloride were dissolved in 4 cc. of pyridine and the reaction mixture was held at 50 C. for 20 hours. The reaction solution was poured into 100 cc. of ice water to form a precipitate which was recrystallized from a mixture of methanol and water. 225 mg. (60% of theory) of the 16,17-acetonide of 21-(pyridine 3 carbonyloxy) 90c fiuoro A pregnadiene-l 113,1604,l7oc-t1iO1-3,2O-di0l16 having a melting point of 225 C. were obtained.

EXAMPLE X The 16,] 7-acet0nide of Z1-(pyridinel-carbonyloxy)-9ufiuoro-A -pregnadielze-1 1 5,16 7a-tri0l-3,20-di0ne 300 mg. of the 16,17-acetonide of 9u-fluoro-A -pregnadiene-i113,16oi,17a-triol-3,20-dione and 135 mg. of the hydrochloride of pyridinel-carboxylic acid chloride were reacted according to the process of Example IX to obtain 340 mg. of the acetonide of 21-(pyridine-4-carbonyloxy)- 904 fluoro A pregnadiene 11,8,160c,17m-1Ii0l-3,20- dione having a melting point of 245-246 C.

EXTERNAL PHARMACEUTICAL COMPOSITIONS A. Oil (wwrer-in-oil emulsion).-5.0 gm. of glycerin monostearate, 30.0 gm. of wool grease and 35.0 gm. of

vaseline were melted was heated to 70 C benzoate was dissolved in stirred until cold.

. Cream gm. of methyl p-hydroxybenzoate in 79.88 at 70" C. The C. and 0.02 gm. of micronized 21-(pyridine-4-carbonyloxy)- 9a fluoro 160a A pregnadiene 115,170:- diol-3,20-dione was uniformly distributed therethrough with an immersion homogenizer. The cream was then stirred until cold and was then rolled.

C. Tinclure.-0.02 gm. of 2 1-(pyridine-4-carbonyloxy) 9a fluoro 16a methyl A pregnadiene 11,8, 17a-diol-3,20-dione and 0.5 gm. of hexachlorophene were dissolved in 65.0 gm. of ethyl alcohol with stirring. While still stirring, 0.2 gm. of Perfume 2422 (Martens) and 34.28 gm. of water were added and the resulting solution was filtered until free from fibers.

Active Substance 24 hr. 48 hr.

s=17. 2 s= Pyridine-et-carboxylic acid ester of dexarnethasone-21.

Acetic acid ester of dena- Inethasone-2l.

Succinic acid ester of deltamethasone-2l.

n= number of rats in group. s= average deviation.

D. Lotion.-2.5 gm. of ce-tylstearyl alcohol (Lanette N) and 2.0 gm. of isopropyl myristate were melted together and then heated to 70 C. The melt was then emulsified at 70 C. into a solution of 0.1 gm. of methyl p-hydroxybenzoate and 4.0 gm. of glycerin dissolved in 91.38 gm. of distilled water. The emulsion was stirred until cold and then 0.02 gm. of micronized 2l-(pyridine- 4 carbonyloxy) 9a fiuoro 16oz methyl A pregnadiene-l l/,l7adiol-3,20-dione was uniformly distributed therethrough with an immersion homogenizer.

E. Aerosol spray.-0.02 gm. of 21 (pyridine 4 carbonyloxy) 90c fiuoro 16a methyl A pregnadiene- 11B,l7a-diol-3,20-dione was dissolved with stirring in a mixture of 30.0 gm. of ethyl alcohol and 38.38 gm. of

filling methods.

F. Suspensiorz.First 0.2 gm. of sodium benzoate and then 0.2 gm. of carboxymethyl cellulose (highly viscous) were dissolved in 87.33 gm. of distilled water. 10.0 gm. of glycerin, 0.75 gm. of polyoXyethylene-sorbitol mono-oleate (Tween 80), 1.5 gm. of finely divided salicylic acid and 0.02 gm. of 2l-(pyridine-4-carbonyloXy)-9a-fiuoro-l6e-methyl A pregnadiene-1lp,17mdiol-3,20-dione were stirred in the solution. The resulting suspension was homogenized and freed from air with a vacuum.

Similar compositions have been prepared with the products of Examples I and III to X with the same concentration of active ingredient.

PHARMACOLOGICAL DATA A. Glucocorticoid activity.-The glucocorticoid activity of the pyridine-4-carboxylic acid ester of dexamethason- 21 was compared to dexamethasone and its acetic acid ester and succinic acid ester. Groups of male rats having Using the method of Porter et al. (Endocrinology, vol. 53, 1953, (reaction integral) obtained Duration of Effect in Days Relative Efiect Overall Activity The results of has only 49% acid ester is only 20.6% as B. Anti-inflammatory activity.The anti-inflammatory activity of the same steroids was determined using the anti-exudative activity against the albuminous edema of By provoking edema at various periods A subplanter injection of 0.1 ml. of a 10% al'buminous solution in 0.85% sodium chloride solution effected the re- 8 of the active products as microcrystalline suspensions in LD of the said ester was 442 rug/kg. determined by a solution of ethanol in 09% sodium chloride soluthe method of Litchfield and Wilcoxan. tion. The release of the edema was effected at 3, 7, 23, Various modifications of the compositions of the in- 47, 95, 119 and 143 hours after the administration of vention may be made without departing from the spirit the active products and the increase in swelling of the or scope thereof and it is to be understood that the inpaw was determined one hour later. The data is sumvention is to be limited only as defined in the appended marized in Table 11. claims.

TABLE IL-ANTI-EXUDATIVE EFFECT Reaction Integral Overall percent X hour Arresting Eflect Percent Reduction in Swelling as Compared With Controls Hours After Administration Dosage in Compound Tested mgjlrg.

Dexamethasone PyridineA-carboxylie acid ester of of dexamethasone.

Succinie acid ester of dexamethasone.

Table II shows that the anti-inflammatory of dexa- We claim:

methasone and its acetic acid and succinic acid ester are 1. A compound of the formula: only 13.1, 41.5 and 46.8%, respectively, of the antiinflammatory activity of the pyridine-4-carboxylic acid ester of dexamethasone.

C. Hypophysis inhibiting activity.-The hypophysis inhibiting activity was determined by the adrenal cortexinvolution shown by the decrease in adrenal weight in rats. Groups of ten healthy male rats having an average beginning weight of 75 to 80 gm. received four doses of the test compounds over a period of 14 days. The compounds were administered intramuscularly as a microcrystalline suspension in 10% ethanol in (1 9% 5 i s; g i f frorln g sodium chloride solution. The control anlmals received ig 6 l a y i a the same volume of the solvent. After 14 days, the rats i t z ig i (130x i j gf gg 3; A i; were killed and the moist weight of the adrenal glands g y y a P was immediately determined. The percentage differences --0 CH3 in weight of the adrenal glands of the animals as compared to the control animals shows the hypophysis inhibiting activity of the test compounds and the results CH3 are reported 111 Table and Y is selected from the group consisting of pyridine- TABLE 111 2,3- and 4-carbonyloxy and pyridine-2,3 and 4-acetoxy.

2. A compound of the formula: Dosage, Percent Reduction of Compound lkg. the Adrenal Glands 5O CH2 Y Compared to Controls CZO f/ 110 l 011 21-(pyridine--carbonyloxy)-9a- 30 31 fluoro-lfia-methyl-n 60 32 pregnadiene-l1,8,17a-diol-3,20- 120 61 "CH: dione. l 1 9u-fluoro-16a-methyl-A 30 28 F pregnadiene-lhifla,21-triol-3,20- O: dione. 120 74 wherein Y is selected from the group consisting of pyri- 60 dine-2,3 and 4-carbonyloxy and pyridine-2,3 and 4- acetoxy.

3. A compound of the formula:

1 The ester was administered at dosages calculated as the free alcohol. Table HI shows that at low dosages (30y/kg. daily), the hypophysis inhibiting activity of the ester and the alcohol are not materially diiierent but at higher dosages, the 21-(pyridine-4-carbonyloxy)-ester has a significantly lower hypophysis inhibiting activity as compared to the 65 o=0 CHz-Y free alcohol as can be seen by the lesser effect on the 110- adrenal glands.

D. Acute t0xicity.-The acute toxicity was determined on groups of 10 male mice having an average beginning weight of 18 to 20 gm. 21-(pyridine-4-carbonyloxy)-9orfluoro-16ot-methyl-A -pregnadiene-l1fl,l7a dio1 3,20- 0: dione in a 1% Tylose solution was administered intraperitoneally at varying dosages with a constant volume of wherein Y is selected from the group consisting of pyri- O.4 ml. per 20 gm. of weight of the mice. The mice dine-2,3 and 4-carbonyloxy and pyridine-2,3 and 4- were kept under observation for seven days and the 75 acetoxy.

wherein Y is selected from the group consisting of pyridine-2,3 and 4-carbonyloxy and pyridine-2,3 and 4-acetoxy.

5. 21 (pyridine 3 carbonyloxy) 9a fiuoro 16w methyl-A -pregnadiene-1 lB,17a-diol-3,20-dione.

6. 21 (pyridine 4 carbonyloxy) 9a fiuoro 16amethyl-A -pregnadiene-l 1,8, l7tz-diol-3,20-dione.

7. 21 (pyridine 2 carbonyloxy) 9a fluoro 16oz methyl-A -pregnadiene-l 1,8, 17oc-diO1-3,20-d10118.

8. 21 (pyridine 3 acetoxy) 90c fluoro 16oz methyl-A -pregnadiene-1 1B, 1 7a-diol-3,20-dione.

9. The 16,17-acetonide of 21-(pyridine-3-carbonyloxy)- 9a-fluoro-A -pregnadiene-l lfl, 16a, 17u-trio1-3,20-dione.

10. The l6,l7-acetonide of 21-(pyridine-4-carbonyloxy) 9a-fluoro-A -pregnadiene-l1,8,l6a,17a-triol-3,20- dione.

11. 21 (pyridine 2 carbonyloxy) 90c A -pregnene-1 1B, 1 7a-diol-3,20-dione.

12. 21 (pyridine 3 carbonyloxy) 9oz fluoro-A pregnene-l1;3,17ot-diol-3,20-dione.

13. 21 (pyridine 4 carbonyloxy) 9oz fiuoro A pregnene-l 1p,17a-dio1-3,20-dione.

14. 21 (pyridine 3 acetoxy) 90c fluoro pregnene-l 1,6, 17a-dioI-3,20-dione.

15. A composition having a high anti-infilammatory activity and a reduced hypophysis inhibiting activity comprising a carboxylic acid ester of the formula:

wherein X and X' form a radical selected from the group consisting of ethylene and vinylene, R is selected from the group consisting of hydrogen and methyl and together with the 17-hydroxy1 group forms the radical and Y is selected from the group consisting of pyridine-2, 3 and 4-carbonyloxy radicals and pyridine-2,3 and 4- acetoXy radicals and a pharmaceutical carrier.

16. The composition of claim 15 wherein the said ester is 21 (pyridine 4 carbonyloxy)-9 x-fiuoro-16a,methyl- A -pregnadiene-l 1B, 1 7a-diol-3,20-di0ne.

17. A method for inhibiting inflammation which comprises administering daily an eifective amount of a carboxylic acid ester of the formula:

([lHz-Y 0:0 ori X -R X 4 3 I F O:

and Y is selected from the group consisting of pyridine-2, 3 and 4-carbonyloxy radicals and pyridine-2,3 and 4- acetoXy radicals.

18. The method of claim 17 wherein the said ester is 21 (pyridine 4 carbonyloxy) 90c fluoro cmethyl-A -pregnadiene-l 1fl,17oc-di0l-3,20-di0116.

Fieser et al.: Steroids, p. 683 and 691 (1959), Reinhold Pub. Co., N .Y.

LEWIS GO'IT S, Primary Examiner. HENRY A. FRENCH, Assistant Examiner. 

17. A METHOF FOR INHIBITING INFLAMMATION WHICH COMPRISES ADMINISTERING DAILY AN EFFECTIVE AMOUNT OF A CARBOXYLIC ACID ESTER OF THE FORMULA 